Moving the Needle: Accelerating Drug Discovery in Nephrology
Authors: James A. Shayman
Journal: Journal of the American Society of Nephrology (2023)

Drug discovery and development is expensive and inefficient. In 2021, 50 novel drugs were approved by the US Food and Drug Administration (FDA). The research expenditure by the 33 members of the PhRMA foundation in that year was 102.3 billion dollars, more than twice the National Institutes of Health budget. New molecular entities that include chemical-based compounds and polypeptides of <40 amino acids in length accounted for most new approvals. 2020 was a typical year for drug approvals related to renal disease represented by lumasiran (for primary hyperoxaluria type 1). While 2021 was a banner year for drugs targeting renal diseases (avacopan for antineutrophil-associated vasculitis, difelikefalin for pruritis in CKD, finerenone for CKD in diabetes, and voclosporin for lupus nephritis), as of late 2022 only terlipressin (for hepatorenal syndrome) had been approved. The 5-year average for drug approvals affecting in the therapeutic area of nephrology is <1% of all approvals, placing nephrology well below oncology, neurology, hematology, rheumatology, infectious disease, cardiology, and metabolism.1 In general, any progress made in the arena of drug development for kidney disease has been the result of the choice of targets by groups outside of the nephrology community. Why has the pursuit of drug discovery and development by our community been so limited? Some potential explanations include the following. First, the renal disorders that many investigators target are chronic and characterized by a long time to a clinically measurable outcome. Thus, a clinical trial design that uses the decline of glomerular filtration rate as a primary end point requires many subjects, a long study period, and significant costs. Second, disproportionate effort has focused on disorders that are better described as clinical syndromes and not mechanistically distinct diseases. The standard nosology for classifying renal disease has not helped in this regard. CKD, end stage renal failure, and polycystic kidney disease are examples of clinical syndromes that are often studied as distinct diseases leading investigators to pursue targets that may at best apply to only a subpopulation of those diagnosed with the disorder. Although some new therapeutics target common pathways such as fibrosis (e.g., sodium-glucose cotransport-2 inhibitors, aldosterone receptor antagonists), opportunities to apply evolving insights from disease-specific pathobiology are often ignored. Many noteworthy examples of such insights are readily apparent and include secondary causes of hypertension, genetic causes of focal segmental glomerular sclerosis, and genetically distinct causes of polycystic kidney disease. Stated differently, opportunities for the discovery and development of targeted therapeutics often arise when a subset of patients with a common syndrome are recognized as having a mechanistically distinct basis for their clinical phenotype, effectively redefining these individuals as having an orphan disease within a larger clinical syndrome. The Orphan Drug Act of 1983 was enacted to incentivize the pursuit of novel treatments for rare diseases, defined as a disease that affects fewer than 200,000 individuals.2 Since 1986, 5477 orphan drug designations have been granted. However, only 111 (2%) of these designations are for drugs targeting kidney disease. If one excludes kidney cancer and solid organ transplantation, only 67 such designations have been granted since the inception of the Orphan Drug Act. Moreover, four disorders (autosomal dominant polycystic kidney disease, Fabry disease, cystinosis, and C3 glomerulopathy) account for 26 of the 67 of these designations, many for the same agent (cysteamine) or for biosimilars (α-galactosidase A). On average, fewer than two orphan disease designations per year since 1986 have been approved for kidney-related disease, with a much smaller fraction of agents receiving these designations eventually reaching regulatory approval. Recent reviews on therapies for rare diseases confirms this dismal track record with orphan drug product approvals by the FDA for kidney disease representing <2% of all approvals. By their analysis of approvals by therapeutic area, renal disease did not merit an individual designation and was relegated to the category of other.3,4 This limited record of accomplishment has occurred despite the recognition that rare diseases account for a significant percent of the burden of kidney disease.5 On the basis of prevalence, mostly every type of glomerulonephritis, including IgA nephropathy, is a rare disease. After diabetes and hypertension, rare diseases account for the next most common cause of ESKD. Inherited rare diseases account for most causes of ESKD in children. Maintaining an accurate compendium of rare kidney diseases has been challenging. Important general efforts have been pursued to harmonize disease nomenclature and include the Encyclopedia for Rare Disease Annotations for Precision Medicine (eRAM) and Orphanet.6 A useful resource is the open-access resource Pharos and the Target Central Resource Database, part of a larger effort by the Illuminating the Druggable Genome Program (IDG).7 This work provides a classification-based schema for cataloging diseases, including rare kidney disorders, into target development groups (TDLs) on the basis of what is known about the molecular target, typically a protein. Greater than one thousand kidney-specific proteins fall within these TDLs (Tclin, Tchem, Tbio, and Tdark), which are defined in Table 1. Table 1 - Tractability for kidney-specific protein targets Target Development Group Definition Kidney-Specific Targets Target Category Tbio Proteins with a defined level of biological understanding but without a reported binding to a small molecular entity 636 Enzyme (104), transcription factor (52), transporter (33), ion channel (12), kinase (4), GPCR (4), epigenetic (2), other (423) Tchem Proteins known to bind small molecules with high affinity 230 Enzyme (83), transporter (23), kinase (19), ion channel (19), transcription factor (12), nuclear receptor (5) epigenetic (4), GPCR (3), other (62) Tclin Proteins that are targets linked to one or more approved drugs 118 Enzyme (31), kinase (17), GPCR (11), transporter (10), ion channel (9), nuclear receptor (5), transcription factor (1), other (34) Tdark Proteins with limited characterization 60 Transporter (5), enzyme (4), transcription factor (1), ion channel (1), GPCR (1), other (48) The Pharos defined target development groups are listed in columns 1 and 2. The associated number of kidney-specific targets and the categories of target proteins are provided in columns 3 and 4. The numbers in parentheses represent the numbers of individually identified proteins within each target category. GPCR, G-protein–coupled receptor. As indicated in Table 1, over one thousand known protein targets have been identified in the kidney, of which only a small percentage are the targets of approved drugs. A larger percentage of these proteins appear to be druggable on the basis of the reported binding of a small chemical entity. The remaining targets have some level of biological characterization with very few having no or limited characterization. Thus, there is significant unexplored opportunity for targeting kidney-specific proteins with novel therapeutics. Although many proteins are not targetable by small molecules or antibodies, it is worth noting that emerging modalities such as targeted protein degradation using proteolysis-targeting chimeras,8 autophagy-targeting chimeras,9 deubiquinating-targeting chimeras,10 and lysosome-targeting chimeras11 offer new avenues for targeting previously undruggable proteins. Despite this less than impressive record, four current trends in the field of drug discovery provide reason for optimism for future success in developing new therapeutics for renal diseases. The first trend is the increasing commoditization of research by pharmaceutical companies. Efforts on target identification and validation as well as early lead discovery are now largely relegated to academic groups and startup ventures. Thus, funding for novel targets can occur through both traditional sources and the private sector. The second trend has been the recognition by academic leaders that drug discovery is an important part of the research mission for universities and institutes. Many of these centers have established infrastructure in support of target identification and druggability, target characterization, lead discovery, the design and synthesis or new analogs, and pharmaceutical disposition (so-called absorption, distribution, metabolism, excretion studies). This has provided academic laboratories the opportunity to pursue high-risk leads before moving them into the commercial sector. The third trend is a growing focus on precision medicine. When successful, precision medicine redefines major clinical syndromes as a collection of mechanistically distinct diseases. In addition, there are increased efforts to identify disease modifiers, providing new insights into the natural history of these disorders. The fourth trend has been the adoption of business models that support the development of therapeutics for rare diseases. Although this trend has accelerated the high pricing of several drugs, it has resulted in the willingness of the commercial sector to invest in the later, more costly stages of drug development. What can the renal community do to make the drug discovery process more efficient, less onerous, and more successful? The following suggestions could help to move the needle. We should support formal efforts to harmonize renal disease nomenclature on the basis of current and evolving insights into their pathogenesis and clinical phenotype. Such harmonization would provide a more accurate understanding of the number and scope of rare diseases of the kidney and would aid in the establishment of disease registries and natural history studies, preclinical proof of concept studies, biomarker discovery, and clinical trial design. We should support training opportunities for early- and mid-career academic renal investigators in drug discovery and development and provide early-stage funding in drug discovery as a catalyst to engage more investigators and target more disorders. We should support the continued development of platforms that accelerate drug discovery and development in renal disease. Examples include the use of kidneys on a chip and inducible pluripotent stem-cell models of renal disease applied to compound library and toxicology screening, the discovery and validation of surrogate markers for progressive kidney diseases, and adaptive trial designs for rare diseases. We should establish best practices for drug development that are specifically applicable to renal disease. The identification of druggable targets on the basis of proof-of-concept studies and the best strategies for the choice and design of therapeutics are important goals. For example, we should discourage the use of phenotypic screens that are not associated with target identification, particularly if no mechanism of action is identified, and encourage the pursuit of killer experiments that can provide a go/no-go decisions. We should encourage renal study sections and editorial boards to adopt and articulate rigorous standards for drug development that align with those in the fields of pharmacology and medicinal chemistry as expectations for funding and publication. These include compound library screening, medicinal chemistry focused on structure activity relationships, pharmacokinetic and pharmacodynamic work, mechanism of action experiments, and toxicology. The implementation of such standards will help to mitigate the well-documented concerns of the pharmaceutical industry of the replication of work reported by academia.12 It is often said that in drug discovery, there are many beginners and few finishers. However, no one ever finished unless they first began.